Anticonvulsant and sedative-hypnotic activity of some novel 3-[5-(4-substituted) phenyl-1,3,4-oxadiazole-2yl]-2-styrylquinazoline-4(3H)-ones

Article abstract of DOI:10.1007/s00044-009-9188-6

A few novel 3-[5-(4-substituted) phenyl-1,3,4-oxadiazole-2-yl]-2-styryl quinazoline-4(3H)-ones were synthesized and evaluated for anticonvulsant, neurotoxicity, sedative-hypnotic, and phenobarbitone-induced hypnosis potentiation test. After i.p. injection to mice at doses of 30, 100, and 300 mg/kg body weight derivatives were examined in the maximal electroshock-induced seizures (MES) and subcutaneous pentylenetetrazole (scPTZ)-induced seizure models in mice. Spectroscopic data were consistence with the newly synthesized compounds. The neurotoxicity was assessed using the Rotorod method. Out of 15 compounds only 7e and 7o showed anticonvulsant activity at various doses in one or more test models. All except 7d, 7m, and 7n exhibited significant sedative-hypnotic activity via actophotometer screen. Central nervous system (CNS)-depressant activity screened with the help of the forced swim method resulted into some potent compounds. No percentage increase in the sleeping time was observed in any of the synthesized compounds evaluated by the phenobarbitone-induced hypnosis potentiation test. On the basis of experimental data, it can be concluded that synthesized compounds possessed relatively better sedative-hypnotic and CNS-depressant activities.

Full text of DOI:10.1007/s00044-009-9188-6

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2010) 19:250–261
DOI 10.1007/s00044-009-9188-6
ORIGINAL RESEARCH
Anticonvulsant and sedative-hypnotic activity of some
novel 3-[5-(4-substituted) phenyl-1,3,4-oxadiazole-2yl]-
2-styrylquinazoline-4(3H)-ones
Sushil K. Kashaw Æ Vivek Gupta Æ Varsha Kashaw Æ
P. Mishra Æ J. P. Stables Æ N. K. Jain
Received: 26 May 2008 / Accepted: 17 March 2009 / Published online: 23 April 2009
¨
Ó Birkhauser Boston 2009
Abstract A few novel 3-[5-(4-substituted) phenyl-1,3,4-oxadiazole-2-yl]-2-styryl
quinazoline-4(3H)-ones were synthesized and evaluated for anticonvulsant, neuro-
toxicity, sedative-hypnotic, and phenobarbitone-induced hypnosis potentiation test.
After i.p. injection to mice at doses of 30, 100, and 300 mg/kg body weight
derivatives were examined in the maximal electroshock-induced seizures (MES)
and subcutaneous pentylenetetrazole (scPTZ)-induced seizure models in mice.
Spectroscopic data were consistence with the newly synthesized compounds. The
neurotoxicity was assessed using the Rotorod method. Out of 15 compounds only 7e
and 7o showed anticonvulsant activity at various doses in one or more test models.
All except 7d, 7m, and 7n exhibited significant sedative-hypnotic activity via
actophotometer screen. Central nervous system (CNS)-depressant activity screened
with the help of the forced swim method resulted into some potent compounds. No
percentage increase in the sleeping time was observed in any of the synthesized
compounds evaluated by the phenobarbitone-induced hypnosis potentiation test. On
the basis of experimental data, it can be concluded that synthesized compounds
possessed relatively better sedative-hypnotic and CNS-depressant activities.
Keywords 4(3H)-quinazolinones Á MES Á
Subcutaneous pentylenetetrazole-induced seizure Á CNS depressant activity
S. K. Kashaw (&) Á V. Gupta Á V. Kashaw Á P. Mishra Á N. K. Jain
Pharmaceutical Chemistry Division, Department of Pharmaceutical Sciences,
Dr. H.S. Gour University, Sagar, India
e-mail: sushilkashaw@gmail.com
J. P. Stables
Preclinical Pharmacology Section, Epilepsy Branch, National Institutes of Health,
Bethesda, MD 20892-9020, USA

Med Chem Res (2010) 19:250–261
251
Introduction
4(3H)-Quinazolinones and related quinazolines are classes of fused heterocycles
that are of considerable interest because of the diverse range of their biological
properties. Among the most important are: anti-tumor (Plescia et al., 1992), anti-
inflammatory (Mukerji et al., 1980), central nervous system (CNS) depressant
(Misra et al., 1982), anthelmintic (Chaurasia and Sharma, 1982), muscle relaxant
(Kumar et al., 1983), hypoglycemic and anti-microbial activities (Saxena et al.,
1992). It was proven that 4(3H)-quinazolinone derivatives possessing a thiazolyl,
thiadiazolyl, and oxadiazolyl moiety at the 3 position of 4(3H)-quinazolinone
exhibit potent CNS activity (Mishra et al., 2006). Among the few reports in the
literature, our attention was drawn to the earlier discovery by scientists that
modification of methyl group present at the second position of 4(3H)-quinazolinone
by some other chemical moiety yielded structural analogues with appreciable
anticonvulsant activity (Boltze et al. 1963; Wolfe et al., 1990). 1,3,4-oxadiazole
itself exhibits CNS activity (Armarego, 1963). The present work is an extension of
our ongoing efforts toward the development and identification of new molecules
possessing CNS activity (Gupta et al., 2008; Jatav et al., 2008a, 2008b). We have
successfully reported the potent activity of some 4(3H)-quinazolinones carrying
1,3,4-thiadiazole group at third position. In hope of getting synergistic response of
4(3H)-quinazolinone nucleus itself, substitution of 1,3,4-oxadiazole nucleus at third
position and chemically modifying second position of 4(3H)-quinazolinone, the
present investigation, potentiated by the aforementioned facts, reports the synthesis,
anticonvulsant, neurotoxicity, CNS depressant, and behavioral study of 15 new
3-[5-(4-substituted)phenyl-1,3,4-oxadiazole-2-yl]-2-styrylquinazoline-4(3H)-ones.
Chemistry
3-[5-(4-substituted)phenyl-1,3,4-oxadiazole-2-yl]-2-styrylquinazoline-4(3H)-ones
(7a–o) were obtained (Fig. 1) by refluxing equimolar amounts of opportune 2-
methyl-3-[5-(4-substituted) phenyl-1,3,4-oxadiazole-2-yl]-quinazoline-4(3H)-ones
(6) and substituted benzaldehyde in glacial acetic acid. 6a–6e was obtained by
refluxing benzoxazinone (5) and 2-amino-5-aryl -1,3,4-oxadiazole (3) in glacial
acetic acid for 6–8 hours. Synthesis of 2-amino-5-aryl -1,3,4-oxadiazole and
benzoxazinone was performed according to the procedure reported previously
(Mishra et al., 2006).
Results and discussion
Initial anticonvulsant activity and neurotoxicity data for the quinazolinone analogs
are reported in Table 3, along with data on phenytoin, carbamazepine, and sodium
valproate. In this series all the quinazolinone analogs showed more potent sedative-
hypnotic and CNS-depressant activity compared with anticonvulsant. In the earlier
reports, it was highlighted that the presence of electron-rich group attached at the

252
Med Chem Res (2010) 19:250–261
CH3COONa
R1
CH=N-NHCONH2
R1
CHO + H2NNHCONH2
2
1
CH3COONa
Br2, CH3COOH
N
N
R1
O
NH2
3
O
N
COOH
AC2O
O
Reflux
NH2
CH3
4
5
N
O
N
N
R1
NH2
O
N
N
R1
H
H
H
R2
H
CH3
Cl
R1
a
b
c
d
e
f
O
6
N
CH3
Cl
Cl
Cl
H
CH3
Cl
R2
CHO
g
h
i
j
k
l
m
n
o
CH3
CH3
CH3
OCH3
OCH3
OCH3
N(CH3)2
H
CH3
Cl
H
CH3
Cl
O
N
N
N
R1
N
O
H
R2
N(CH3)2 CH3
N(CH3)2 Cl
7
Fig. 1 Scheme for the synthesis of titled compounds (7a–7o)
para position of the aryl ring showed increased potency in the MES screen
(Dimmock et al., 1995a, 1995b).
Only two compounds, 7e and 7o, were found to exhibit anticonvulsant activity in
MES screen; however, compound 7o showed potency in scPTZ screen. Compound
7e and 7o displayed activity in the MES screen after 0.5 hours at 300 mg/kg and
100 mg/kg, respectively. Both 7e and 7o showed rapid onset of action, but only 7o
showed long duration of activity. The only scPTZ active compound showed rapid
onset as well as long duration of anticonvulsant activity at 300 mg/kg. Compounds

Med Chem Res (2010) 19:250–261
253
7f, 7j, 7n, and 7o showed neurotoxicity after 0.5 hours at 100 mg/kg or 300 mg/kg
body weight. All the compounds were screened for behavior study and CNS-
depressant activity. In the behavioral study using actophotometer scoring technique
(Table 4), compounds showed decrease in locomotor activity between 30–56%, in
which 30% was the lowest and 56% was the maximal decrease in locomotor
activity. 7d, 7m, and 7n were not significantly active in this screening at 1 hour.
Compounds 7c, 7f, and 7i exhibited more than 50% decrease in locomotor activity
(p \ 0.05) after 1 hour. In a similar study using swim pool test, the immobility time
after administration of the test compounds were compared with carbamazepine
(Table 5). Except for 7g, 7m, 7n, and 7o other tested compounds were found to
exhibit potent CNS-depressant activity (p \ 0.05) as indicated by increased
immobility time. Generally we found that bulkier compounds exhibited good
CNS activity. Present pharmacological studies explored that substitution of 4(3H)-
quinazolinone at third position by 1,3,4-oxadiazole and second position by styryl
moiety leads to the development of new compounds with potent sedative-hypnotic
and CNS depressant activity compared with anticonvulsant activity.
Conclusions
Based on the experimental results, it may be concluded that the synthesized new
chemical entities showed potent sedative-hypnotic and CNS depressant activity
compared with anticonvulsant activity.
Experimental
Chemistry
Melting point was determined in one end open capillary tubes on a Buchi 530
melting point apparatus and are uncorrected. Infrared (IR) spectra were recorded for
1
the compounds on Perkin Elmer Spectrum RXI Spectrophotometer in KBr. H
nuclear magnetic resonance (1HNMR) spectra were recorded for the compounds on
Advance bruker (300 MHz) instrument. Chemical shifts are reported in parts per
million (ppm) using tetramethylsilane (TMS) as an internal standard. Elemental
analysis (C, H, and S) were undertaken with Elemental vario EL III Carlo Erba 1108
analyzer. The purity of the compounds was confirmed by thin layer chromatography
using silica gel glass plates and a solvent system of benzene: ethanol (8:2). The
spots were developed in iodine chamber and visualized under ultraviolet lamp.
The structure of new compounds was elucidated by analytical and spectroscopic
measurements. The IR spectra showed the C=O peak at 1701 cm-1, C=O str. at
1580 and C=C stretching (Alkene) vibration at 1630 cm-1. The 1H NMR spectra of
compounds 7a–o are consistent with the trans olefinic structure: b-olefinic protons
appeared as doublets at d 6.296-6.980 (J = 16.2 Hz as required for a trans
structure), whereas the a-olefinic hydrogen were found along with aromatic
multiplet because of the deshielding effect of two quinazolinone nitrogens.

254
Med Chem Res (2010) 19:250–261
Table 1 Physical data of 3-[5-(4-substituted) phenyl-1,3,4-oxadiazole-2-yl]-2-styryl quinazoline-4(3H)-
one
Comp. Mol. formula
Mol. wt. M.P. (°C) % Yield Quassi-molecular Elemental analysis
ion peak
(% calculated/% found)
7a
7b
7c
7d
7e
7f
C24H16N4O2
392.42
406.45
210
240*
43.29% 392
C (73.46/73.45)
N (14.28/14.25)
H (4.11/4.10)
C
C
C
C
C
C
C
C
C
C
C
C
25H18N4O2
52.74% 406
6.9% 427
49.8% 427
47.3% 441
52.05% 461
61.94% 406
45.15% 420
46.93% 441
36.65% 422
49.2% 436
57.47% 457
C (73.88/73.86)
N (13.78/13.75)
H (4.46/4.44)
24H15N4O2Cl 426.5
24H15N4O2Cl 426.5
25H17N4O2Cl 440.5
24H14N4O2Cl2 461.31
238–240
195*
C (67.53/67.51)
N (13.13/13.11)
H (3.54/3.52)
C (67.53/67.50)
N (13.13/13.11)
H (3.54/3.50)
215
C (68.11/68.09)
N (12.71/12.69)
H (3.89/3.86)
185*
C (62.49/62.47)
N (12.15/12.13)
H (3.06/3.01)
7g
7h
7i
25H18N4O2
406.45
420.47
195–197
185*
C (73.88/73.86)
N (13.78/13.75)
H (4.46/4.41)
26H20N4O2
C (74.27/74.25)
N (13.33/13.31)
H (4.79/4.75)
25H17N4O2Cl 440.5
260*
C (68.11/68.09)
N (12.71/12.69)
H (3.89/3.86)
7j
25H18N4O3
422.45
436.47
210*
C (71.08/71.05)
N (13.26/13.24)
H (4.29/4.25)
7k
7l
26H20N4O3
218–220
215*
C (71.55/71.53)
N (12.84/12.82)
H (4.62/4.60)
25H17N4O3Cl 456.5
C (65.72/65.70)
N (12.26/12.24)
H (3.75/3.71)
7m
26H21N5O2
435.49
180* 54%
435
C (71.71/71.69)
N (16.68/16.65)
H (4.86/4.83)

Med Chem Res (2010) 19:250–261
255
Table 1 continued
Comp. Mol. formula
Mol. wt. M.P. (°C) % Yield Quassi-molecular Elemental analysis
ion peak
(% calculated/% found)
7n
7o
a
C
27H23N5O2
449.52
183–185
180*
44.8% 449
C (72.14/72.23)
N (15.58/15.57)
H (5.16/5.13)
C26H20N5O2Cl 469.5
63.7% 470
C (66.45/66.43)
N (14.90/14.89)
H (4.29/4.26)
Elemental analyses for C, H and N were within 0.4% of the theoretical value
* Melting point of the compound at their decomposition
Synthesis of 3-[5-(4-substituted)phenyl-1,3,4-oxadiazole-2yl]-2-styrylquinazo-
line-4(3H)-ones took after procedure.
Synthesis of 4-substituted benzaldehyde semicarbazone (2)
Semicarbazide hydrochloride (0.01 M) and sodium acelate (0.02 M) was dissolved
in 15–20 ml of distilled water placed in flat-bottomed flask. Required aromatic
aldehyde (0.01 M) was dissolved in aldehyde-free alcohol. This solution was added
slowly to the solution of semicarbazide hydrochloride. The precipitate, which get
separated, was filtered, dried, and recrystallized from hot ethanol (95%).
Synthesis of 2-amino-5-aryl-1,3,4–oxadiazols (3)
Semicarbazone (2) (0.01 M) and sodium acetate (0.02 M) was dissolved in 30–
40 ml of glacial acetic acid with continuous stirring. Bromine (0.7 ml in 5 ml of
GAA) was added slowly to it. Solution was stirred for 1 hour and then poured on
crushed ice. The resulting solid was separated, dried, and recrystallized from hot
ethanol (95%).
Synthesis of 2-methyl benzoxazin-4(3H)-one (5)
Anthranilic acid (4) (0.01 M, 1.8 g) was taken in acetic anhydride and refluxed
under anhydrous conditions for 4 hours. Excess of acetic anhydride was then
distilled off under reduced pressure. Obtained product was immediately used for
next step.
Synthesis of 2-methyl-3-[5-(4-substituted)phenyl-1,3,4-oxadiazole-2-yl]-
quinazoline-4(3H)-ones (6)
To the mixture of benzoxazinone (5) and 2-amino-5-aryl -1,3,4-oxadiazole (0.01 M)
in 10 ml of glacial acetic acid was added and refluxed under anhydrous condition
for 4 hours. After cooling it was poured into crushed ice. The solid separated out

256
Med Chem Res (2010) 19:250–261

Med Chem Res (2010) 19:250–261
257
was filtered thoroughly washed with cold distilled water, dried, and recrystallized
from hot ethanol (95%).
Synthesis of title compounds (7)
Equimolar amounts (0.012 M) of 2-methyl-3-[5-(4-substituted)phenyl-1,3,4-oxadi-
azole-2-yl]-quinazoline-4(3H)-one and the opportune benzaldehyde were reacted in
glacial acetic (5.2 ml) under reflux for 18 hours. A sticky oily matter was obtained,
which was purified to remove impurities to get final product. Final compound was
dried and recrystallized from hot ethanol. Physico-chemical and spectral data of the
compounds are presented in Tables 1 and 2.
Pharmacology
The anticonvulsant evaluation were undertaken using the reported procedure
(Swinyard et al., 1961; White et al., 1995a, 1995b). Male albino mice (CF-1 strain
Table 3 Anticonvulsant activity and minimal motor impairment of 3-[5-(4-substituted)phenyl-1,3,4-
oxadiazole-2-yl]-2-styryl quinazoline-4(3H)-one
Code no.
Intraperitoneal injection in micea
MES screen
0.5 h
scPTZ screen
Neurotoxicity screen
4 h
0.5 h
4 h
0.5 h
4 h
7a
–
–
–
–
–
–
–
–
–
7b
–
–
–
–
–
7c
–
–
–
7d
–
–
–
–
–
–
–
7e
300
–
–
–
–
–
7f
–
–
–
100
–
–
7g
–
–
–
–
–
7h
–
–
–
–
–
–
7i
–
–
–
–
–
–
7j
–
–
–
–
300
–
–
7k
–
–
–
–
–
7l
–
–
–
–
–
–
7m
–
–
–
–
–
–
7n
–
–
–
–
100
100
100
100
–
–
7o
100
30
30
–
100
30
100
–
300
–
300
–
100
100
300
–
Phenytoin
Carbamazepine
Sodium vaporate
a
100
300
300
–
Doses of 30, 100, and 300 mg/kg were administered. The animals were examined 0.5 and 4 hours after
injections were made. The dash (–) indicates an absence of activity at maximum dose administered
(300 mg/kg)

258
Med Chem Res (2010) 19:250–261
or swiss, 18–25 g) and rats (Sprague-Dawley or Wistar, 100–150 g) were used as
experimental animals. The tested compounds were suspended in polyethylene
glycol 400.
Anticonvulsant screening
Initially all of the compounds were administered i.p. in a volume of 0.01 ml/g body
weight for mice and 0.004 ml/g body weight for rats at doses of 30, 100, and
300 mg/kg to one to four animals. Activity was established using the MES and
scPTZ test and these data are presented in Table 3.
Neurotoxicity screening
Minimal motor impairment was measured in mice by the Rotorod test. The mice
were trained to stay on an accelerating Rotorod that rotated at 6 rpm. The rod
diameter was 3.2 cm. Neurotoxicity was indicated by the inability of the animal to
maintain equilibrium on the rod for at least 1 minute in each of the three trials.
Table 4 Behavioral study of 3-[5-substituted 1,3,4- oxadiazole-2 yl]-2- styryl quinazoline-4(3H)-ones
Compounda
Activity scoreb
% Inhibition
Control (24 h before)
Posttreatment
0.5 h after
1 h after
7a
450.24 14.74
439.12 10.14
316.62 10.36
420.12 11.04
395.56 8.93
405.55 21.32
342.14 11.74
416.50 13.41
460.91 11.14
350.12 15.72
382.67 9.32
445.67 10.70
362.02 24.91
416.04 11.26
239.40 15.76
546.40 31.12
465.82 14.19NS
401.09 12.13
281.39 9.69
343.36 7.28
233.19 10.11
103.78 4.89
261 10.12NS
172.36 3.28
137.16 10.26
241.36 6.21
362.48 13.36
140.18 17.64
165.52 10.15
177.42 21.91
172.50 4.52
200.73 22.34NS
266.36 11.89NS
72.62 6.19
48
47
51
38
45
53
48
40
56
41
42
50
30
37
49
70
7b
7c
7d
398.12 15.12
304.08 10.24
300.91 26.52
361.82 14.10NS
430.20 21.20NS
359.81 9.18
7e
7f
7g
7h
7i
7j
292.36 4.65
7k
310.22 16.79
297.41 19.84
286.48 26.27
381.82 9.69
7l
7m
7n
7o
Phenytoinc
187.62 15.20
251.02 12.32
164.10 30.11
a
Compound were tested at a dose of 100 mg/kg (i.p.)
b
Each score represents the mean SEM of six mice, significantly different from the control score at
\0.05, and NS indicates not significant at p [ 0.05 (Student’s t test)
c
Tested at 25 mg/kg i.p

Med Chem Res (2010) 19:250–261
259
Behavioral testing
The titled compounds (100 mg/kg) were screened for their behavioral effect using
actophotometer (Boissoer and Simon, 1965) at 30 minutes and 1 hour after drug
administration. The behavior of animals inside the photocell was recorded as a
digital score. Increased scores suggest good behavioral activity. The activity of the
compounds were at maximum at 1 hour; therefore, the activity values at 1 hour was
used to calculate % decrease in locomotor activity. The control group of animals
was administered PEG 400. The observations are shown in Table 4.
CNS-depressant activity
The forced swim pool method described previously by Porsolt et al. (1978) was
followed. Wistar rats were placed in chamber (diameter 45 cm, height 20 cm)
containing water up to a height of 15 cm at 25 2°C. Two swim sessions were
conducted an initial 15 minutes pretest, followed by a 5-minute test session
24 hours later. The animals were drug administrated (100 mg/kg) the test compound
i.p. 30 minutes before the test session. The period of immobility (passive floating
Table 5 CNS study on 3-[5-substituted 1,3,4-oxadiazole-2-yl]-2- styryl quinazoline-4(3H)-ones by
forced swim pool test
Codea
Immobility timeb (s)
Control (24 h before)
Posttreatment (60 min after)
PEG
110.32 8.26
60.15 13.14
121.52 11.28
113.31 11.93
175.41 7.74
88.30 10.23
69.12 16.42
147.01 21.27
134.31 18.72
98.20 15.80
113.18 7.62
121.73 5.91
123.34 6.23
41.12 14.28
113.23 21.22
103.23 10.82
138.82 15.09
127 .51 2.48 NS
113.14 13.25
160.05 13.18
151.11 11.90
217.93 14.21
135.18 15.61
100.12 4.91
7a
7b
7c
7d
7e
7f
7g
152.39 17.24NS
163.21 11.64
150.76 13.29
163.75 20.18
182.82 18.95
184.36 9.32
7h
7i
7j
7k
7l
7m
50.23 10.17NS
125.42 7.12 NS
121.21 11.16 NS
240.30 14.10
7n
7o
Carbamazapinec
a
Compounds were tested at a dose of 100 mg/kg (i.p.)
b
Each value represents the mean SEM of six rats significantly different from the control at p \ 0.05
and NS denotes not significant at p \ 0.05 (Student’s t test)
c
Tested at 25 mg /kg (i.p.)

260
Med Chem Res (2010) 19:250–261
without struggling, making only those movements that are necessary to keep its
head above the surface of water) during the 5-minute test period were measured.
The results are presented in Table 5.
Acknowledgment The authors acknowledge the assistance of the Antiepileptic Drug Development
Program, Epilepsy Branch, Preclinical Pharmacology Section, NIH, USA.
References
Armarego WL (1963) Quinazolines. Adv Heterocycl Chem 11:253–309. doi:10.1016/S0065-2725(08)
60527-9
Boissoer JR, Simon P (1965) Arch Int Pharmacodyn Ther 158:212–214
Boltze KH, Dell HD, Lehwald H, Loranz D, Ruberg-Schweer M (1963) Substituted 4-Quinazolinone
derivatives as hypnotics and anticonvulsants. Arzneim-Forsch Drug Res 13:688–692
Chaurasia MR, Sharma SK (1982) Pharmacological evaluation of 2-substituted (1,3,4) thiadiazolo
quinazolines. J Indian Chem Soc 59:370–376
Dimmock JR, Pandeya SN, Quail JW, Pugazhenthi U, Allen TM, Kao GY, Balzarini J, Clercq ED
(1995a) Evaluation of the semicarbazones, thiosemicarbazones and bis-carbohydrazones of some
aryl alicycylic ketones for anticonvulsant and other biological properties. Eur J Med Chem 30:303–
314. doi:10.1016/0223-5234(96)88238-9
Dimmock JR, Sidhu KK, Tumber SD, Basran SK, Chen MJ, Quail W, Yang J, Rozas I, Weaver DF
(1995b) Some aryl semicarbazones possessing anticonvulsant activities. Eur J Med Chem 30:287–
301. doi:10.1016/0223-5234(96)88237-7
Gupta A, Mishra P, Kashaw SK, Jatav V, Stables JP (2008) Synthesis and anticonvulsant activity of some
novel 3-aryl amino/amino-4-aryl-5-imino-Delta(2)-1,2,4-thiadiazoline. Eur J Med Chem 43:749–
754. doi:10.1016/j.ejmech.2007.05.008
Jatav V, Mishra P, Kashaw S, Stables JP (2008a) CNS depressant and anticonvulsant activities of some
novel 3-[5-substituted 1,3,4-thiadiazole-2-yl]-2-styryl quinazoline-4(3H)-ones. Eur J Med Chem
43:1945–1954. doi:10.1016/j.ejmech.2007.12.003
Jatav V, Mishra P, Kashaw S, Stables JP (2008b) Synthesis and CNS depressant activity of some novel 3-
[5-substituted 1,3,4-thiadiazole-2-yl]-2-styryl quinazoline-4(3H)-ones. Eur J Med Chem 43:135–
141. doi:10.1016/j.ejmech.2007.02.004
Kumar P, Dhawan KN, Vrat S, Bhargava KP, Kishore K (1983) Synthesis of 6-substituted 2-phenyl-3-(5-
substituted mercapto-1,3,4, thiadiazol-2-yl)quinazolin-4-(3H)-ones as antitubercular agents. Arch
Pharm 316:759. doi:10.1002/ardp.19833160906
Mishra P, Jatav V, Kashaw SK (2006) Some novel 2-Methyl-3-(1’3’4’-thiadiazoyl)-4-(3H) quinazoli-
nones with anticonvulsant and CNS depressant activity. J Indian Chem Soc 83:1165–1170
Misra S, Satsangi RK, Tiwari SS (1982) Synthesis and CNS activities of some 2-alkyl-3(2-substituted
indol-3-yl)-methyl, 6-substituted-quinazolin-4(3H)-ones. Pol J Pharmacol Pharm 34:441–447
Mukerji DD, Nautiyal SR, Prasad CR, Dhawan BN (1980) CNS-depressant activity of some newly
synthesised 4(3H)-quinazolones. Indian J Med Res 71:480–482
Plescia S, Daidone G, Raffa D, Bajardi ML, Caruso AV (1992) Synthesis and pharmacological study of
some 3-(isoxazol-5-yl)-quinazolin-4(3H)-ones. Farmaco 47:465–475
Porsolt RD, Anton G, Blanet N, Jalbre M (1978) Behavioural despair in rats: a new model sensitive to
antidepressant treatments. Eur J Pharmacol 47:379–386. doi:10.1016/0014-2999(78)90118-8
Saxena S, Verma M, Saxena AK, Shanker K (1992) 1,3,4-oxidiazole thiones as inflammation inhibitors.
Indian J Pharm Sci 54:1–3
Swinyard EA, Clark LD, Miyahara JT, Wolf HH (1961) Studies on the mechanism of amphetamine
toxicity in aggregated mice. J Pharmacol Exp Ther 132:97–102
White HS, Johnson M, Wolf HH, Kupferberg HJ (1995a) The early identification of anticonvulsant
activity: role of the maximal electroshock and subcutaneous pentylenetetrazol seizure models. Ital J
Neurol Sci 16:73–77. doi:10.1007/BF02229077
White HS, Woodhead JH, Franklin MR (1995b) General principals: experimental selection, quantification
and evaluation of antiepileptic drugs. In: Antiepileptic drugs. New York, Raven Press, pp 99–110

Med Chem Res (2010) 19:250–261
261
Wolfe JF, Rathman TL, Sleevi MC, Campbell JA, Greenwood TD (1990) Synthesis and anticonvulsant
activity of some new 2-substituted 3-aryl-4(3H)-quinazolinones. J Med Chem 33:161–166. doi:
10.1021/jm00163a027